Inverse agonism at alpha(2)-adrenoceptors in native tissue

Several alpha(2)-adrenoceptor antagonists have inverse agonist properties i n cell culture systems, usually expressing high levels or a constitutively active form of alpha(2)-adrenoceptors. In characterizing the binding of a, adrenoceptor agonists to rat brain tissue sections, we found that condition s known to alter agonist affinity for these receptors, particularly the add ition of 100 mu M GTP, altered the binding of the alpha(2)-adrenoceptor ant agonist [H-3](1,4-benzodioxan-2-methoxy-2-yl)-2-imidazoline hydrochloride ( RX821002). In further studies, we found that under our conditions [H-3]RX82 1002 demonstrates inverse agonist properties at alpha(2)-adrenoceptors. Thi s is the first demonstration of inverse agonism at alpha(2)-adrenoceptors i n native tissue. We found that the alpha(2)-adrenoceptor antagonist, (2S,12 bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro-2H-benzo(b)furo(2,3-a) quinazoline)-2,4'-pyrimidin-2'-one (MK-912), did not have clearly discernib le inverse agonist properties and acted as a neutral antagonist in these st udies. On the other hand, the antagonist rauwolscine actually displayed par tial agonist properties in our studies. These findings indicate that the in verse agonist properties of alpha(2)-adrenoceptor antagonists can be demons trated in native tissue, as well as in tissue culture, and they strengthen the idea that inverse agonist properties may be of physiological and pharma cological importance. (C) 2000 Elsevier Science B.V. All rights reserved.